Porcine insulin zinc suspension: what the FDA reviewed for dog products
4 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Porcine insulin zinc suspension, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Canine; Dogs and Cats.
Products
- Vetsulin® (NADA/ANADA 141-236)
Vetsulin® NADA 141-236, Original approval, April 01, 2004; sponsor Intervet, Inc.; species: Canine; foi_id 778; FDA PDF
Indication
Reduction of hyperglycemia and hyperglycemia-associated clinical signs in dogs with diabetes mellitus.
Dose regimen
1 IU insulin/kg body weight plus a body weight-dependent dose supplement (Table 1), Subcutaneous injection (U-40 syringe), 2 to 5 cm from the dorsal midline, alternating sides, Once daily initially, concurrently with or right after a meal; twice daily (each dose 25% less than the once-daily dose) if duration of insulin action is inadequate, Dose supplement 1 IU (<10 kg), 2 IU (10-11 kg), 3 IU (12-20 kg), 4 IU (>20 kg); dose titrated to clinical signs, urinalysis and glucose curve (nadir 60 to 160 mg/dL); chronic therapy
The initial recommended VETSULIN dose is 1 IU insulin/kg body weight plus a body weight-dependent dose supplement as shown in Table 1.
Target-animal safety
Insulin is an endogenous hormone whose mechanisms of action and effect have been studied for over 80 years. Insulin tolerance in the dog and the effects of hypoglycemia that results from overdosage have been well described.
| Finding | Quote |
|---|---|
| Field study: dose-related hypoglycemia and occasional owner-observed injection site reactions were the primary events | Porcine insulin zinc suspension safety in dogs was confirmed by the US field study. Dose-related hypoglycemia and occasional owner-observed injection site reactions were the primary events reported. |
| Foreign pharmacovigilance (1995-2001, 19 dogs): insulin overdose caused fatal profound hypoglycemia in four dogs | After an overdose of insulin, four dogs developed profound hypoglycemia which resulted in death in all four dogs. |
| Foreign pharmacovigilance: head/neck edema in two dogs (resolved on switching insulin) and a fibrous injection-site lump in one dog | Two dogs developed edema of the head and neck that resolved when they were switched to another insulin product, and one dog developed a fibrous lump at the injection site. |
Effectiveness
Multi-location (9 investigators) open-label field study, May 1997 to May 2001, in client-owned dogs with naturally occurring diabetes mellitus; compared with the predictable history of the disease (21 CFR 514.117(b)(4)(iv)); Dose Determination Period (5 to 151 days, mean 42) followed by a 60-day Study Period with evaluations at Times 1, 2 and 3.; n = 66 enrolled; 53 completed; primary endpoint: 12-hour blood glucose curve means and mean nadirs, presence/absence of polyuria, polydipsia and ketonuria, and investigator assessment of glycemic control vs pre-treatment (Time 0); result: Mean blood glucose curve concentration fell from 370 +/- 100 mg/dL (Time 0) to 151 +/- 75 (Time 1), 185 +/- 92 (Time 2) and 184 +/- 87 mg/dL (Time 3); mean nadir from 315 +/- 93 to 93 +/- 35, 120 +/- 62 and 119 +/- 60 mg/dL. Polyuria improved in 96%/82%/94%, polydipsia 96%/86%/96%, ketonuria 80%/86%/83% at Times 1/2/3. Investigator-assessed adequate control 100% (53/53), 66% (35/53), 75% (40/53).
Animals: A total of 66 client-owned dogs were enrolled, and 53 completed the effectiveness and safety study.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Hypoglycemia (with or without clinical signs) | 35.5% (22/62) | Hypoglycemia with or without associated clinical signs occurred in 35.5% (22/62) of the dogs at various times during the study. | |
| Disorientation and collapse | 16.1% (10/62) | Disorientation and collapse were reported less frequently and occurred in 16.1% (10/62) of the dogs. | |
| Seizure (presumptive hypoglycemia-induced; one death) | Two dogs | Two dogs had a seizure and one dog died during the seizure. Although never confirmed, the presumptive diagnosis was hypoglycemia-induced seizures. | |
| Injection site reactions (swollen, painful, sore, bleb under the skin) | Seven owner reports | Seven owners recorded the following observations about the injection site on the home monitoring forms: swollen, painful, sore, and a bleb under the skin. | |
| Hematuria, vomiting, diarrhea, pancreatitis, hepatopathy/pancreatitis, cataracts, urinary tract infections | The following clinical observations also occurred in the field study following treatment with VETSULIN and may be directly attributed to the drug or may be secondary to the diabetic state or other underlying conditions in the dogs: hematuria, vomiting, diarrhea, pancreatitis, non-specific hepatopathy/pancreatitis, development of cataracts, and urinary tract infections. |
Extraction notes: Original approval. No pharmacokinetic data and no margin-of-safety (dose-multiple) study: target animal safety rests on literature, the field study, an unpublished long-term study (up to 448 days) and post-study extended use (41 to 1720 days; mean survival 838 days in 53 dogs). Adverse reaction denominators are 62 dogs assessed for safety (66 treated); no control group. Species/Class is stated as 'Canine' in the summary.
Vetsulin® NADA 141-236, Supplemental approval, April 10, 2013; sponsor Intervet, Inc.; species: Dogs and Cats; foi_id 780; FDA PDF
Indication
Reduction of hyperglycemia and hyperglycemia-associated clinical signs in dogs and cats with diabetes mellitus. Effect of supplement: change in the specification for non-extractable (NE) insulin.
Dose regimen
0.5 IU insulin/kg body weight (initial dose, dogs), Subcutaneous injection (U-40 syringe), Once daily initially, with or right after a meal; twice daily (each dose 25% less) if duration of action inadequate, Cats: 1 to 2 IU per injection twice daily at approximately 12 hour intervals
The initial recommended VETSULIN dose is 0.5 IU insulin/kg body weight. Initially, this dose should be given once daily concurrently with, or right after a meal.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other | onset of action median 1 hour (range 0.5 to 2 hours) | Pharmacodynamic (plasma glucose) parameter; 12 fasted healthy Beagles, single SC 0.5 IU/kg, NE insulin content 61% | Onset of action ranged from 0.5 to 2 hours (median 1 hour); time to glucose nadir ranged from 1 to 10 hours (median 8 hours); and duration of action ranged from 10 to 24 hours (median 12 hours). |
| other | time to glucose nadir median 8 hours (range 1 to 10 hours) | Pharmacodynamic parameter; 12 fasted healthy Beagles, single SC 0.5 IU/kg, NE insulin content 61% | Onset of action ranged from 0.5 to 2 hours (median 1 hour); time to glucose nadir ranged from 1 to 10 hours (median 8 hours); and duration of action ranged from 10 to 24 hours (median 12 hours). |
| other | duration of action median 12 hours (range 10 to 24 hours) | Pharmacodynamic parameter (time for glucose to return to 80% of baseline); 12 fasted healthy Beagles, single SC 0.5 IU/kg | Onset of action ranged from 0.5 to 2 hours (median 1 hour); time to glucose nadir ranged from 1 to 10 hours (median 8 hours); and duration of action ranged from 10 to 24 hours (median 12 hours). |
| other | glucose nadir 51 ± 9.4 mg/dL (mean ± SD) | Pharmacodynamic parameter; healthy dogs (n=12), single SC 0.5 IU/kg; Table 1 | Glucose nadir (mg/dL) 51 ± 9.4 [mean ± SD] |
| other | onset of action median 1 hour (range 0.5 to 2 hours) | CATS: pharmacodynamic parameter; 12 fasted healthy adult cats, single SC 0.5 IU/kg, NE insulin content 61% (onset based on 12 cats) | Onset of action ranged from 0.5 to 2 hours (median 1 hour); time to glucose nadir ranged from 2 to 6 hours (median 2 hours); and duration of action ranged from 8 to 24 hours (median 12 hours). |
| other | time to glucose nadir median 2 hours (range 2 to 6 hours) | CATS: pharmacodynamic parameter; healthy cats, single SC 0.5 IU/kg (9 cats evaluable) | Onset of action ranged from 0.5 to 2 hours (median 1 hour); time to glucose nadir ranged from 2 to 6 hours (median 2 hours); and duration of action ranged from 8 to 24 hours (median 12 hours). |
| other | duration of action median 12 hours (range 8 to 24 hours) | CATS: pharmacodynamic parameter; healthy cats, single SC 0.5 IU/kg (9 cats evaluable) | Onset of action ranged from 0.5 to 2 hours (median 1 hour); time to glucose nadir ranged from 2 to 6 hours (median 2 hours); and duration of action ranged from 8 to 24 hours (median 12 hours). |
| other | glucose nadir 34 ± 7.1 mg/dL (mean ± SD) | CATS: pharmacodynamic parameter; healthy cats (n=9), single SC 0.5 IU/kg; Table 2 | Glucose nadir (mg/dL) 34 ± 7.1 [mean ± SD] |
Effectiveness
Laboratory pharmacodynamic study (S11376-00-CAN-OTH-CN, Angers, France) in fasted healthy adult Beagles given a single subcutaneous 0.5 IU/kg dose of VETSULIN with non-extractable insulin content at the lower end (61%) of the proposed 58%-72% specification; plasma glucose sampled to 24 h. A parallel study was run in 12 healthy cats.; n = Twelve (healthy adult Beagles); primary endpoint: Glucose nadir, time to nadir, onset of action (10% reduction) and duration of action (return to 80% of baseline); result: Dogs: onset median 1 h (0.5-2), time to nadir median 8 h (1-10), duration median 12 h (10-24), nadir 51 +/- 9.4 mg/dL (49% of baseline); hypoglycemia (<40 mg/dL) in three dogs, one with trembling. Cats: nadir 34 +/- 7.1 mg/dL, all cats hypoglycemic, three removed for oral glucose.
Twelve fasted healthy adult Beagles received a single subcutaneous injection of VETSULIN at a dose of 0.5 IU/kg.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Hypoglycemia (<40 mg/dL) - dogs, PD study | three dogs (one with trembling) | Hypoglycemia was recorded in three dogs, one of which had trembling as an associated clinical sign. | |
| Hypoglycemia with clinical signs - cats, PD study | all cats | Hypoglycemia was recorded in all cats. Clinical signs of hypoglycemia included: weakness, trembling, loss of balance, hypothermia, blindness, disorientation, slight convulsions, loss of consciousness, vomiting, and uncontrolled defecation. |
Extraction notes: Supplement changing the non-extractable insulin specification; the only studies are laboratory pharmacodynamic studies in healthy dogs (n=12) and cats (n=12, 9 evaluable), which are recorded as 'effectiveness' and as 'other' PK-type (pharmacodynamic) parameters. No target animal safety studies were required (cross-referenced to earlier FOI summaries). Adverse reactions are from healthy laboratory animals, no control group.
Vetsulin® NADA 141-236, Supplemental approval, February 03, 2014; sponsor Intervet, Inc.; species: Dogs and Cats; foi_id 781; FDA PDF
Indication
Reduction of hyperglycemia and hyperglycemia-associated clinical signs in dogs and cats with diabetes mellitus. Effect of supplement: 2.7 mL cartridge presentation for the VETPEN automatic injection device.
Dose regimen
0.5 IU insulin/kg body weight (initial dose, dogs), Subcutaneous injection (U-40 syringe or VETPEN with 2.7 mL cartridge), Once daily initially, with or right after a meal; twice daily (each dose 25% less) if duration of action inadequate, Cats: 1 to 2 IU per injection twice daily at approximately 12 hour intervals
The initial recommended VETSULIN dose is 0.5 IU insulin/kg body weight. Initially, this dose should be given once daily concurrently with, or right after a meal.
Effectiveness
Dogs: 21-day open-label, multi-site (12 French practices) field study (EX-5156-00, March-May 2010) of VETPEN insulin-pen usability in client-owned diabetic dogs stabilized on VETSULIN for at least 4 months; 1-week adjustment period; success defined as at least 70% positive responses to three yes/no questions (owner could learn the pen; pen well tolerated; diabetes control not negatively impacted).; n = 40 enrolled (38 in effectiveness evaluation); primary endpoint: Percentage of positive responses to the three final questions (success threshold 70% each); result: 37/38 owners (97.4%) learned to use the pen; 35/38 (92.1%) said it was well tolerated; for 34/38 dogs (89.5%) investigators judged diabetes control not negatively affected. Companion cat study (EX-5157-00, 36 cats): 100%, 94.4% and 97.2%.
Of 40 dogs enrolled in the study, two dogs whose owners did not adjust to using the insulin pen during the adjustment period were excluded from the effectiveness analysis. Therefore, all 40 dogs enrolled in the study were included in the safety evaluation and 38 were included in the effectiveness evaluation. Thirty-four of the 38 dogs completed the Study Day 21 visit. Four dogs were withdrawn between Study Days 8 and 21 and were included in the analysis on the basis of owner responses and investigator evaluations when they were withdrawn. Thirty-seven of the 38 owners (97.4%) said they were able to learn how to use the insulin pen. Thirty-five of the 38 owners (92.1%) said the insulin pen was well tolerated by the dogs. For 34 of the 38 dogs (89.5%), the investigators said that the control of diabetes was not negatively affected by the use of the insulin pen.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Loss of diabetic control - dogs | 10 dogs (3 withdrawn) | Loss of diabetic control was reported in 10 dogs, 3 of which were withdrawn from the study. | |
| Injection site reactions (edema; crusting) - dogs | Two dogs | Two dogs had injection site reactions: edema in one dog and two instances of crusting in another. | |
| Poor appetite and weight loss - dogs | one dog | Poor appetite and weight loss was reported in one dog. | |
| Loss of diabetic control - cats | three cats | Loss of diabetic control was reported in three cats, all of which resolved after dose adjustment while still using the insulin pen. | |
| Hypoglycemia (glucose <= 50 mg/dL) - cats | one cat | Hypoglycemia (glucose ≤ 50 mg/dL) was reported in one cat. |
Extraction notes: Supplement adding a cartridge/pen presentation; the studies are device-usability field studies in dogs (n=40) and cats (n=36), not drug effectiveness trials. No PK data (the batch plan's PK-sentence count does not correspond to any PK content) and no target animal safety studies (cross-referenced). Adverse reactions are uncontrolled owner/investigator reports.
Vetsulin® NADA 141-236, Supplemental approval, March 24, 2008; sponsor Intervet, Inc.; species: Dogs and Cats; foi_id 779; FDA PDF
Indication
Reduction of hyperglycemia and hyperglycemia-associated clinical signs in dogs and cats with diabetes mellitus. Effect of supplement: new starting dose in dogs and use in cats.
Dose regimen
0.5 IU insulin/kg body weight (initial dose, dogs), Subcutaneous injection (U-40 syringe), Once daily initially, concurrently with or right after a meal; twice daily if duration of action inadequate, Cats: initial dose 1 to 2 IU per injection twice daily at approximately 12 hour intervals; dose adjusted to clinical signs, urinalysis and glucose curves
The initial recommended VETSULIN dose is 0.5 IU insulin/kg body weight. Initially, this dose should be given once daily concurrently with, or right after a meal.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other | peak activity between 1.5 and 8 hours | Cats; subcutaneous administration; pharmacodynamic (glucose-lowering) statement from literature, not a sponsor PK study | In cats, the peak activity following subcutaneous administration of VETSULIN occurs between 1.5 and 8 hours, and the duration of activity varies between 8 and 12 hours. |
| other | duration of activity between 8 and 12 hours | Cats; subcutaneous administration; pharmacodynamic statement from literature (intermediate-acting insulin) | In cats, the peak activity following subcutaneous administration of VETSULIN occurs between 1.5 and 8 hours, and the duration of activity varies between 8 and 12 hours. |
Target-animal safety
Insulin is an endogenous hormone whose mechanisms of action and effect have been extensively studied. Insulin tolerance in the cat and the effects of hypoglycemia that result from overdosage have been well described.
| Finding | Quote |
|---|---|
| Cats: hypoglycemia, lethargy, vomiting and two injection site reactions were the primary reactions in the US field studies | Porcine insulin zinc suspension safety in cats was confirmed by the US field studies. Hypoglycemia, lethargy, vomiting, and two injection site reactions were the primary reactions reported. |
| Long-term support from Australian field studies (up to 52 weeks) and US extended use (up to 258 weeks) | Additional support for the safety of VETSULIN is provided by data from field studies conducted in Australia that included long term evaluation of cats (up to 52 weeks of treatment) and US field study post-study extended use (up to 258 weeks of treatment). |
Effectiveness
Cats, pivotal field effectiveness and safety dose-confirmation study (Study 2017-003-00, April 2005 to September 2006, 13 US sites) in client-owned diabetic cats; all cats treated (historical control per 21 CFR 514.117(b)(4)(iv)); initial 1 to 2 IU per injection twice daily, adjusted to effect; 60-day primary period with evaluation to Day 180; repeated-measures mixed models (LOCF).; n = 78 cats enrolled; 77 in effectiveness analysis; primary endpoint: Change from Day 0 in investigator visual analogue scale (VAS) of diabetes control, mean blood glucose and mean blood glucose nadir (10-hour curves); fructosamine secondary; result: LS-mean VAS fell from 93.8 to 31.2 (Day 60) and 25.0 (Day 180); mean blood glucose from 394.1 to 210.8 mg/dL (Day 60) and 212.1 (Day 180); nadir from 343.3 to 145.7 mg/dL (Day 60); all P<0.001. Cats with mean glucose <300 mg/dL: 5.2% (Day 0) to 75.0% (Day 60); nadir <200 mg/dL: 0% to 72.4%. Fructosamine 607.3 to 453.7 (Day 60). Four cats (5%) went into remission.
Description of Test Animals: The study included 78 client owned diabetic cats (53 male and 25 female - all neutered) representing various breeds ranging in age from 3 to 17.5 years and ranging in weight from 1.9 to 10.8 kg. A total of 77 cats were included in the analysis of effectiveness.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Hypoglycemia (blood glucose <50 mg/dL, any) - cats | 61 cats | Hypoglycemia (defined as blood glucose <50 mg/dL) occurred in 61 cats at some time during the study. | |
| Hypoglycemia with clinical signs - cats | 16.7% (13/78) | Fifteen instances of hypoglycemia with associated clinical signs were reported in 13 cats (16.7%, 13/78). | |
| Polyneuropathy - cats | 4 cats | Polyneuropathy was reported in 4 cats. Two cases occurred while the dose was still being adjusted. | |
| Vomiting - cats (Table 14: instances, number of cats) | 27 instances in 23 cats | Vomiting 27 23 | |
| Lethargy - cats (Table 14: instances, number of cats) | 21 instances in 16 cats | Lethargy 21 16 | |
| Diarrhea / abnormal stools - cats (Table 14: instances, number of cats) | 19 instances in 13 cats | Diarrhea / abnormal stools 19 13 |
Extraction notes: Dog portion contains no new studies: the starting dose was lowered from 1 IU/kg plus supplement to 0.5 IU/kg based on literature and re-evaluation of field-study dose data (182 of 253 doses <1.0 IU/kg). Effectiveness, adverse reactions and target animal safety recorded here come from the CAT studies (pivotal Study 2017-003-00, n=78; a pilot study, n=14, also summarized); the n_dogs field therefore holds cats. Table 14 rows are quoted as flattened text: column order is Clinical Sign, Instances, # of cats (n=78). PK entries are literature pharmacodynamic statements for cats.
Reproduce: foi_structured_search(query="Porcine insulin zinc suspension") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).